Thioformamide derivatives

ABSTRACT

PCT No. PCT/EP91/00019 Sec. 371 Date Aug. 20, 1992 Sec. 102(e) Date Aug. 20, 1992 PCT Filed Jan. 8, 1991 PCT Pub. No. WO91/10652 PCT Pub. Date Jul. 25, 1991.   &lt;IMAGE&gt;  (I)  Thioformamide compounds of formula (I) are disclosed in which R is alkyl, Y is methylene, ethylene or a direct bond, A is optionally substituted phenyl or pyridyl, R1 is hydrogen and R2 is N-alkylsulphonyl-, N-phenylsulphonyl-N&#39;-alkylamidino or an arylsulphonyl group; R1 and R2 may both independently represent alkyl- or arylsulphonyl groups.

This invention relates to new therapeutically useful thioformamidederivatives, to processes for their preparation and to pharmaceuticalcompositions containing them.

The thioformamide derivatives of the present invention are thosecompounds of formula (I), hereinafter depicted wherein: R represents analkyl group; A represents a phenyl group which is optionallysubstituted, by one or more substituents selected from, for example,halogen atoms and cyano, nitro, trifluoromethyl, carbamoyl, carboxyl,alkoxycarbonyl and alkylsulphonyl groups or, preferably, a heterocyclylgroup, preferably selected from quinolin-3-yl, isoquinolin-4-yl,pyridazin-4-yl, pyrimidin-5-yl, pyrazin-3-yl, indol-3-yl, thiazol-5-yl,and, more especially, pyridyl, e.g. pyrid-3-yl or pyrid-4-yl, optionallysubstituted by an alkyl or alkoxy group, or by a halogen atom; Yrepresents a direct bond or an ethylene or, preferably, methylene group;and either:

(1) R¹ represents hydrogen and R² represents:

i) a group of formula --CXNHR³, wherein R³ is an alkyl group and X is agroup of formula ═NSO₂ R⁴, wherein R⁴ is alkyl or phenyl; or

ii) a group of formula --SO₂ R⁵, wherein R⁵ represents:

a) a naphthyl or phenyl group optionally substituted by one or morehalogen atoms, hydroxy, alkoxy, C₃₋₆ cycloalkoxy, alkyl, C₂₋₄ alkenyl,cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl, amino,alkylamino, dialkylamino, alkoxycarbonylamino, alkanoylamino,dialkanoylamino, benzoylamino, carbamoyl, N-(optionallyhydroxyalkyl)carbamoyl or N,N-di(optionally hydroxyalkyl)carbamoylgroups, or amino or carbamoyl groups N,N-disubstituted by a C₃₋₆alkylene chain one or more of whose methylene groups may have beenreplaced by an oxygen or sulphur atom or by an imino or alkyliminogroup;

b) a pyridyl or thienyl group; or

c) an alkyl group optionally substituted by one or more halogen atoms,phenyl, naphthyl, pyridyl, hydroxy, alkoxy, C₃₋₆ cycloalkoxy, alkyl,C₂₋₄ alkenyl, cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl,amino alkylamino, dialkylamino, alkoxycarbonylamino, alkanoylamino,dialkanoylamino, benzoylamino, carbamoyl, N-(optionallyhydroxyalkyl)carbamoyl or N,N-di(optionally hydroxyalkyl)carbamoylgroups, or amino or carbamoyl groups N,N-disubstituted by a C₃₋₆alkylene chain, one or more of whose methylene groups may have beenreplaced by an oxygen or sulphur atom or an imino or alkylimino group;

(2) R¹ and R² both independently represent a group of formula --SO₂ R⁵,as defined above; or

(3) R¹ and R² together with the nitrogen to which they are attached froma group of formula (IA) wherein each group R⁹ is independently hydrogenor alkyl and Q is oxygen, sulphur or a group of formula NR⁹ or (CH₂⁹)_(n), wherein n is 0, 1 or 2;

wherein all alkyl groups and moieties, including those in alkoxy,alkoxycarbonyl and alkanoyl groups, are straight-chain or branched, and,unless otherwise specified, contain one to about six carbon atoms; andsalts thereof.

Particularly important classes of compounds of formula (I) exhibit oneor more of the following features:

i) R represents a methyl or ethyl group;

ii) A represents a pyrid-3-yl or pyrid-4-yl group;

iii) Y represents a methylene group;

iv) R₁ represents a hydrogen atom;

v) R³ represents a methyl group;

vi) R⁴ represents a methyl or phenyl group;

vii) R⁵ represents:

a) a phenyl or naphthyl (especially 1-naphthyl) group optionallysubstituted by one or more halogen (especially fluorine or chlorine)atoms or nitro, cyano, alkoxy (especially methoxy) or dialkylamino(especially dimethylamino) groups;

b) a pyrid-3-yl or thien-2-yl group; or

c) an alkyl group of up to 4 carbon atoms; and/or

viii) the group of formula (IA) is a 3,5-dioxomorpholino group; theother symbols being as hereinbefore defined, and their pharmaceuticallyacceptable salts.

The presence of an axocyclic aminoethyl group on the ring creates anisomeric centre in the molecule which in association with the adjacentasymmetric ring carbon atom leads to 4 stereoisomers which, optionally,can be separated into 2 racemic pairs. The racemic pair and enantiomersin which the --(CH₂)₂ NR¹ R² and --CSNHR groups are in the transrelationship are preferred. In certain cases the substituents A, R, R¹and R² can also contribute to stereoisomerism. All such forms areembraced by the present invention.

Particularly important compounds of the present invention include thefollowing:

1H(±)-trans-2-(N-methyl-N'-benzenesulphonyliminoureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1I(±)-trans-2-(N-methyl-N'-methanesulphonyliminoureido)ethyl-N-methyl-1-(3-pyridyl)-cyclohexanecarbothioamide

1J(±)-trans-2-benzenesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1K(±)-trans-2-methanesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1L(±)-trans-2-(4-fluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1M(±)-trans-2-(4-nitrobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1N(±)-trans-2-(4-chlorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1O(±)-trans-2-(4-methoxybenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1P(±)-trans-2-(2-thiophenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1Q(±)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1R(±)-trans-2-(3,4-difluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1S(±)-trans-2-(5-dimethylamino-1-naphthalenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

1T(±)-trans-2-(3,5-dioxomorpholino)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2A (±)trans-2-(propylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2B(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2C(±)-trans-2-(butylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2D(±)-trans-2-(fluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2E(±)-trans-2-(3-cyanobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2F(±)-trans-2-(3-benzenesulphonyl)aminomethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2G(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2H(±)-trans-2-(4-fluorobenzenesulphonyl)aminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide

2I(±)-trans-2-(3-pyridinesulphonylaminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide

2J(-)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2K(-)-trans-2-(4-fluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2L(-)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide

2M(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(4-pyridyl)cyclohexanecarbothioamide

as well as their stereoisomeric forms and pharmaceutically acceptablesalts thereof.

Letters 1H to 1T and 2A to 2M are allocated to compounds for ease ofreference in other parts of the specification.

Compounds within the scope of the present invention exhibit positivepharmacological activities as demonstrated by tests which are believedto correlate to pharmacological activity in humans and other animals.

For example, the compounds have valuable pharmacological properties, inparticular properties which are indicative of utility in the treatmentand/or prophylaxis of disorders associated with:

(1) vascular smooth muscle contraction including hypertension and othercardiovascular disorders such as congestive heart failure, andconditions associated with tissue ischaemia such as angina, peripheralvascular disease and cerebrovascular disease;

(2) respiratory smooth muscle contraction including reversible airwaysobstruction and asthma;

(3) contraction of smooth muscle of gastrointestinal tract, urinarybladder and uterus, including peptic ulcers, irritable bowel syndromeand diverticular disease; irritable bladder syndrome; and prematurelabour.

For example, compounds of general formula (I) were submitted to:

Vaso-relaxant Activity Tests.

The test methods used were adapted from those described by Winslow et al[Eur.J.Pharmacol., 131, 219-228 (1986)] and Karaki [J.Pharmacol.Methods, 18, 1-21 (1987)] for differentiating vaso-relaxant activity.

Test A: Activity against contractions induced by low K⁺ concentrationsin the isolated rat aorta

Thoracic aorta was removed from rats and transverse strips, denuded ofendothelium, were suspended in a bath containing Krebs solution. Thetension was recorded and a contraction induced by addition of 20 mM K⁺(potassium ion) to the bathing solution. The test compound was added tothe bath as a solution in increasing cumulative concentration. Theconcentration in the bathing solution of the test compound which reducedthe K⁺ -induced contraction by 90% was determined and expressed in μM asthe effective concentration (EC₉₀), given in Table 1.

                  TABLE 1                                                         ______________________________________                                                       Activity                                                                      Test A                                                                Compound                                                                              EC.sub.90 μM                                                ______________________________________                                               1H      0.3                                                                   1I      0.03                                                                  1J      0.0003                                                                1K      0.17                                                                  1L      0.007                                                                 1M      0.3                                                                   1N      0.03                                                                  1O      0.3                                                                   1P      0.001                                                                 1Q      0.03                                                                  1R      0.01                                                                  1S      1                                                                     1T      1                                                              ______________________________________                                    

Test B: Activity against contractions induced by high K⁺ concentrationsin isolated rat aorta

The test method was as in Test A with the exception that contractionswere induced by addition of 60 mM K⁺ to the bathing solution. Thecumulative addition of the solutions of the test compound was conductedand the concentration in the bath reducing the K⁺ -induced contractionby 90% was found and expressed as the EC₉₀. For each compound tested itwas greater than 30 μM.

The compounds of general formula (I) can be prepared by the applicationand adaptation of known methods, for example as hereinafter identified.

By the term "known methods" as used in this specification is meantmethods heretofore used or described in the literature.

According to a feature of the present invention, compounds of formula(I), wherein R¹ is hydrogen and R² is a group of formula --C(═NSO₂R⁴)NHR³, as hereinbefore defined, are prepared by the reaction ofcompounds of formula (V), hereinafter depicted, wherein R, Y, A and R⁴are as hereinbefore defined, with a compound of general formula:

    R.sup.3 NH.sub.2                                           (VI)

wherein R³ is as hereinbefore defined. The reaction is carried out in ainert organic solvent e.g. ethanol at a temperature of from 0° C. to 80°C., preferably at reflux.

According to a further feature of the invention compounds of formula(I), wherein R, A and Y are as hereinbefore defined and one or both ofR¹ and R² represents a group --SO₂ R₅, as hereinbefore defined, aresynthesized from compounds of formula (I) wherein one of R¹ and R² ishydrogen, or from a compound of formula (II), wherein Y, A and R are ashereinbefore defined, by reaction with a compound of formula:

    R.sup.2 SO.sub.2 Cl                                        (VIII)

wherein R⁵ is as hereinbefore defined, in the presence of an anhydrousinert organic solvent e.g. dichloromethane or tetrahydrofuran. Thereaction is effected, optionally in the presence of an acid acceptor,for example a teritary amine, e.g. triethylamine, or an inorganic base,e.g. sodium bicarbonate, at a temperature of from -30° C. to +30° C.

According to a further feature of the invention, compounds of formula(I), wherein R¹ and R² form part of a ring of formula (IA) and R, A andY are as hereinbefore defined, are synthesized from compounds of formula(II), wherein Y, A and R are as hereinbefore defined, by reaction with acompound of formula (IX) wherein Q and R⁹ are as hereinbefore defined.The reaction is preferantially carried out in an inert organic solvente.g. toluene, at reflux, in the presence of 1,2-dichlorobenzene to aidsolubility.

The intermediate compounds and the starting materials may be prepared bythe application or adaptation of known methods, for example as indicatedin the following Examples and Reference Examples.

For example, compounds of formula (V) can be synthesised from compoundsof formula (II), hereinafter depicted, wherein Y, A and R are ashereinbefore defined, by reaction with a compound of formula:

    (CH.sub.3 S).sub.2 C═NSO.sub.2 R.sup.4                 (VII)

wherein R⁴ is as hereinbefore defined. The reaction is carried out in ainert organic solvent e.g. ethanol at a temperature of from 0° C. to 80°C.

Compounds of formula (II), wherein A, Y and R are as hereinbeforedefined, can be prepared from the corresponding compounds of formula(X), hereinafter depicted, wherein A, Y and R are as hereinbeforedefined, by reduction with a complex metal reducing agent, such as analuminium hydride (e.g. lithium aluminium hydride) in a dry organicsolvent, such as an ether (e.g. tetrahydrofuran) at elevatedtemperature, preferably from 40° to 80° C.

Compounds of formula (X), wherein A, Y and R are as hereinbeforedefined, may be prepared by the reduction of the corresponding compoundsof general formula (XI), with a complex metal reducing agent, such as analuminium hydride (e.g. lithium aluminium hydride) in a dry inertorganic solvent, such as an ether (e.g. tetrahydrofuran) at roomtemperature

This reaction preferentially gives the reduced product (K) in which the--CSNHR group bears a trans relationship to the --CH₂ CN group.

The compounds of formula (XI), wherein Y, A and R are as hereinbeforedefined, may be prepared by the reaction of a compound of generalformula (XII), hereinafter depicted, wherein A, Y and R are ashereinbefore defined, with a compound of general formula:

    (R.sup.6 O).sub.2 P(O)CH.sub.2 CN                          (XIII)

wherein R⁶ represents an alkyl group of 1 to 4 carbon atoms, preferablya methyl or ethyl group. The reaction is generally carried out in thepresence of a base, preferably sodium hydride, in an ethereal solvent(e.g. tetrahydrofuran) and preferably at a temperature of from 20° C. to100° C.

Compounds of general formula (XII), wherein A, Y and R are ashereinbefore defined may be prepared by the reaction of a compound ofgeneral formula (XIV), hereinafter depicted, wherein A and Y are ashereinbefore defined, with a compound of the general formula:

    R--N═C═S                                           (XV)

wherein R is as hereinbefore defined. The reaction is generally carriedout in an anhydrous inert organic solvent such as tetrahydrofuran,dimethylformamide or hexamethylphosphoramide, or a mixture of thesesolvents, at a temperature from -80° C. to +50° C., in the presence ofan inorganic base such as potassium tert.-butoxide, or an organo-lithiumderivative such as n-butyllithium, or of sodium hydride.

Compounds of formula (XIV), wherein A is as hereinbefore defined in Y isa methylene or ethylene group, can be made via adehydrobromination/rearrangement reaction of compounds of formula(XVIII), hereinafter depicted, wherein A is as defined above and Y¹ ismethylene or ethylene. This may be initiated by a bromido extractingagent such as a silver salt (e.g. silver perchlorate) and carried out inan inert anhydrous solvent (for example an ether such astetrahydrofuran).

Compounds of formula (XVIII), wherein A and Y¹ are as defined above, canbe made by the addition of hypobromous acid across the double bond ofcompounds of formula (XIX), hereinafter depicted, wherein A and Y¹ areas defined above. This may be done by reaction with a brominating agent(e.g. 1,3-dibromo-5,5-dimethylhydantoin) in an aqueous acidic medium,optionally in the presence of a cosolvent.

Compounds of formula (XIX), wherein A and Y¹ are as defined above, canbe made via a coupling reaction between a compound of formula (XX),hereinafter depicted, (typically made in situ by the reaction of acompound of formula (XXI), hereinafter depicted, wherein Y¹ is asdefined above and R⁸ and Z are conventional groups present in a Wittigreagent and its phosphonium salt precursor [e.g. phenyl and brominerespectively] with a strong base, such as potassium t-butoxide, in ananhydrous solvent, such as tetrahydrofuran, preferably under an inertatmosphere) and a compound of formula:

    A-CHO                                                      (XXII)

wherein A is as defined above.

Alternatively, compounds of formula (XIV), wherein A and Y are ashereinbefore defined, can be made from compounds of formula (XXIII),wherein A and Y are as defined above. This is typically carried out inthe presence of a strongly acidic agent (e.g. phosphorus pentoxide orsulphuric acid), optionally in a solvent (such as toluene) and atelevated temperature.

Compounds of formula (XXIII) can be made by reaction of a compound offormula:

    A-Hal                                                      (XXV)

wherein A is as defined above and Hal is a halogen, preferably bromineor chlorine atom, in the presence of a strong base, such as an alkyllithium (e.g. butyllithium), with a compound of formula (XXIV), whereinY is as defined above, in an inert solvent such as an ether (e.g.diethyl ether) or a hydrocarbon (e.g. toluene).

Alternatively, compounds of general formula (XII), wherein A and Y areas hereinbefore defined and R is methyl, can be prepared from compoundsof general formula (XVI), wherein A and Y are as defined above and R⁷ isan alkyl group of 1 to 4 carbon atoms or a benzyl or carboxymethylradical, by reaction with methylamine. The reaction is generally carriedout with an excess of amine, without a solvent or in an inert organicsolvent such as an ether (e.g. tetrahydrofuran) an aromatic hydrocarbonor an alcohol or a mixture of these solvents at a temperature from roomtemperature to 130° C., optionally under pressure, and the amine may beadded in an alcoholic solution, preferably ethanol.

It may be advantageous for the thiol formed during the reaction to befixed in the form of a heavy metal salt using a thiol acceptor such asmercuric chloride.

Compounds of formula (XVI), wherein Y, A and R⁷ are as hereinbeforedefined may be prepared by the reaction of compounds of formula (XIV),wherein Y and A are as hereinbefore defined, with carbon disulphidefollowed by reaction with a compound of formula:

    R.sup.7 -X                                                 (XVII)

wherein R⁷ is as hereinbefore defined and X is halogen, preferablychlorine, bromine or iodine, or a readily displaceable ester group suchas methanesulphonyloxy or 4-toluenesulphonyloxy. The reaction isgenerally carried out in an anhydrous inert organic solvent such astetrahydrofuran, to which hexamethylphosphoramide may be added, at atemperature from -80° C. to +50° C. in the presence of an organic basesuch as potassium tert.-butoxide, or an organo-lithium derivative suchas butyllithium, or sodium hydride.

By the term "pharmaceutically acceptable salts" as used in thisspecification is meant salts the anions or cations of which arerelatively innocuous to the animal organism when used in therapeuticdoses so the the beneficial pharmaceutical properties of the parentcompounds of general formula (I) capable of forming salts are notvitiated by side-effects ascribable to those anions or cations.

It is to be understood that, where in this specification reference ismade to compounds of formula (I), it is intended to refer also, wherethe context so permits, to their pharmaceutically acceptable salts.

Suitable acid addition salts for use in pharmaceuticals may be selectedfrom salts derived from inorganic acids, for example hydrochlorides,hydrobromides, phosphates, sulphates and nitrates, and organic acids,for example oxalates, lactates, tartrates, acetates, salicylates,citrates, propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoates, gentisates anddi-p-toluoyltartrates.

Suitable salts with bases include alkali metal (e.g. sodium andpotassium), alkaline earth metal (e.g. calcium and magnesium), ammoniumand amine (e.g. diethanolamine, triethanolamine, octylamine, morpholineand dioctylmenthylamine) salts.

As well as being useful in themselves as active compounds, salts of thecompounds of general formula (I) capable of forming salts with acids orbases are useful for the purposes of purification of the parentcompounds of general formula (I), for example by exploitation of thesolubility differences between the salts and the parent compounds, bytechniques well known to those skilled in the art.

The thioformamide derivatives of general formula (I) obtained by theaforedescribed processes can be purified by the usual physical methods,in particular crystallisation and chromatography especially to resolvemixtures of enantiomers using a chiral column. ##STR2##

The following Examples and Reference Examples illustrate the preparationof compounds according to the present invention and their intermediates.

All N.M.R. spectra were recorded at 200 MHz. The chemical shifts areexpressed in ppm relative to tetramethylsilane. Abbreviations in thetext are as follows:

s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublets,ddd=doublet of doublets of doublets, dt=doublet of triplets, dq=doubletof quartets, m=multiplet, c=unresolved complex peak, br=broad single.

The expression "m/z" indicates the peak assigned to the molecular ion inthe mass spectrum.

EXAMPLE 1

Compound 1H

To a solution of(±)-trans-2(2-(N-benzenesulphonyl-S-methylisothioureido)ethyl)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (280 mg, 0.57 mmol) in ethanol (5 ml) was added a 33%ethanolic solution of methylamine (1 ml) and the mixture heated atreflux for 6 hr, cooled and concentrated in vacuo to give a pale yellowoil. The oil was purified by flash chromatography over silica gel usingethyl acetate/methanol (9:1) as eluent to give(±)-trans-2-(N-methyl-N'-benzenesulphonyliminoureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (100 mg), as a white solid, m.p. 163°-164° C.;

[N.M.R.(CDCl₃): 1.0-1.6 (m,5H), 1.6 (m,1H), 1.8-2.0 (m,2H), 2.8 (t, 3H),2.9-3.0 (m,2H), 3.05(t, 3H), 3.1-3.2 (m, 2H), 7.2 (q, 1H), 7.4 (m, 3H),7.8 (d, 3H), 8.4 (d, 1H), 8.6 (d,1H), 8.8 (br s, 1H)

Found C, 57.7; H,6.6; N, 14.4; S, 13.3%

C₂₃ H₃₁ N₅ O₂ S₂ requires C, 58.3; H, 6.6; N, 14.8; S, 13.5%].

EXAMPLE 2

Compound 1I

To a solution of(±)-trans-2-(2-(N-methanesulphonyl-S-methylisothioureido)ethyl)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (220 mg, 0.5 mmol) in ethanol (5 ml) was added a 33%solution of methylamine in ethanol (1 ml) and the solution heated atreflux for 5 hr. After cooling, the solution was concentrated in vacuoto give a light brown oil. The oil was purified by flash chromatographyover silica gel using ethyl acetate/methanol (95:5) as eluent to give(±)-trans-2-(N-methyl-N'-methanesulphonyliminoureido)ethyl-N-methyl-1-(3-pyridyl)-cyclohexanecarbothioamide (100 mg), m.pt 125°-126° C.;

[N.M.R. (CDCl₃): 1.3-1.7 (m,7H), 1.75 (m,1H), 2.15 (m, 1H), 2.6 (m, 1H),2.9(d, 3), 2.95 (m,1H), 2.96 (s, 3H), 3.1 (d, 3H), 3.25 (m,2H), 7.33 (q,1H), 7.4 (br s, 1H), 7.8(dt, 1H), 8.55 (dd, 1H), 8.65 (d, 1H)

Found: C, 51.4; H, 7.2; N, 16.65; S, 15.25%

C₁₈ H₂₉ N₅ O₂ S₂.1/2H₂ O requires: C, 52.5; H,7.1; N, 17.0; S, 15.6%].

EXAMPLE 3

Compounds 1J to 1S

To a solution of(±)-trans-2-aminoethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide(0.5 g, 1.8 mmol) in dichloromethane (10 ml) at 0° C. was added, withstirring, triethylamine (0.25 ml, 1.8 mmol) and then benzenesulphonylchloride (0.22 ml, 1.8 mmol). After stirring for 1 hr at 0° C., thesolution was allowed to warm slowly to room temperature and stirred fora further 1 hr. The solution was treated with water (30 ml) anddichloromethane (30 ml). The organic layer was collected, washed withwater, dried (MgSO₄) and concentrated in vacuo to give an orange solid.The residue was subjected to flash chromatography over silica gel usingmethanol/ethyl acetate (5:95) as eluent, to give(±)-trans-2-benzenesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (130 mg), m.pt 109°-110° C.;

[N.M.R.(CDCl₃): 1.25-1.55 (m, 6H), 1.8(m,1H), 2.1-2.2 (m,2H), 2.5, (m,1H), 2.8 (m, 2H), 3.0 (m, 1H), 3.1(d, 3H), 4.9 (br t, 1H), 7.2 (br s,1H), 7.3(q, 1H), 7.5-7.6 (m, 3H), 7.8 (dt, 1H), 7.85(d,2H), 8.5 (dd,1H), 8.6 (d, 1H)

Found: C, 60.3; H, 6.76; N, 9.8%

C₂₁ H₂₇ N₃ O₂ S₂ requires: C, 60.4; H, 6.5; N, 10.1%].

By proceeding in a similar manner but replacing the benzenesulphonylchloride with the appropriate sulphonyl chloride, there were prepared:

i)(±)-trans-2-methanesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt 90° C.;

[N.M.R. (CDCl₃): 1.3-1.4(m,1H), 1.4-1.7(m,6H), 1.9-2.05(m, 1H),2.1-2.2(m,1H) 2.6-2.7(m,1H), 2.9(s, 3H), 3.0-3.1 (m, 2H), 3.1(d, 3H),3.2(m, 1H), 4.8 (br t, 1H), 7.3 (q, 1H),7.5 (br s, 1H), 7.85 (dt, 1H),8.5 (dd, 1H), 8.65 (d, 1H)

Found: C, 53.6; H, 7.2; N, 11.1; S, 17.0%

C₁₆ H₂₅ N₃ O₂ S₂ requires: C, 54.0; H, 7.1; N, 11.8; S, 18.0%];

ii)(±)-trans-2-(4-fluorobenzenesulphonyl)-aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt. 64°-66° C.;

[N.M.R.(CDCl₃): 1.2-1.9(m,7H), 2.1 (m,1H), 2.55 (m,1H), 2.7-3.0 (m, 4H),3.1(d, 3H), 5.2 (br t, 1H), 7.1-7.3 (m, 3H), 7.4 (br s, 1H), 7.7-7.9 (m,3H) 8.4 (dd, 1H), 8.6 (d, 1H)

Found: C, 57.9; H, 6.3; N, 9.1; S, 14.2%

C₂₁ H₂₆ FN₃ O₂ S₂ requires: C, 57.9; H, 6.0: N, 9.65; S, 14.7%];

iii)(±)-trans-2-(4-nitrobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt 108°-109° C.

[N.M.R.(CDCl₃): 1.2-1.9(m,8H), 2.0-2.2 (m, 1H), 2.4-2.6 (m, 1H), 2.7-3.0(m, 3H), 3.1 (d,3H), 5.8 (br t, 1H), 7.2-7.4 (m, 2H), 7.8 (d,1H), 8.0(d, 2H), 8.4 (dd, 3H), 8.6(d, 1H)

Found: C, 54.2; H, 5.6; N, 11.8; S, 13.8%

C₂₁ H₂₆ N₄ O₄ S₂ requires: C, 54.3; H, 5.7; N, 12.1; S, 13.9%];

iv)(±)-trans-2-(4-chlorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, mpt 106°-107° C.;

[N.M.R.(CDCl₃): 1.3-1.6 (m, 7H), 1.8 (m,1H), 2.1-2.2(m,1H),2.5-2.55(m,1H), 2.75-2.9(m, 2H), 2.95-3.05(m, 1H), 3.1 (d, 3H), 5.1 (brs, 1H),7.25(br s, 1H), 7.3 (q, 1H), 7.5(d, 2H), 7.8 (m, 3H), 8.5 (dd,1H), 8.65 (d, 1H)

Found: C, 55.3; H, 5.8; N, 9.2; S, 13.9%

C₂₁ H₂₆ ClN₃ O₂ S₂ requires: C, 55.8; H, 5.8; N, 9.3; S, 14.2%];

v)(±)-trans-2-(4-methoxybenzenesulphonyl)-aminomethyl-N-methyl-1-(3-pyridylcyclohexanecarbothioamide, m.pt 95°-96° C.;

[N.M.R.(CDCl₃): 1.25-1.6 (m,7H), 1.8 (m,1H), 2.05-2.15(m, 1H),2.52-2.6(m, 1H), 2.8-2.9 (m, 2H), 2.9-3.0(m, 1H), 3.1 (d, 3H), 3.9 (s,3H),4.85 (br t, 1H), 7.0(d, 2H), 7.25-7.35 (m, 3H), 7.8(d, 2H), 8.5 (dd,1H), 8.6 (d, 1H)

Found: C, 59.5; H, 6.7; N, 9.5; S, 14.0%

C₂₂ H₂₉ N₃ O₃ S₂ requires: C, 59.0; H, 6.5; N, 9.4: S, 14.3%];

vi)(±)-trans-2-(2-thiophenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt 96°-98° C.;

[N.M.R.(CDCl₃): 1.3-1.6 (m,7H), 1.8-1.9(m, 1H), 2.1-2.15 (m, 1H),2.5-2.6 (m, 1H), 2.8-2.9 (m, 1H), 2.9-3.0 (m, 1H), 3.0-3.1 (m, 1H),3.1(d, 3H), 5.15 (br t, 1H), 7.1 (dd, 1H), 7.3 (q, 1H), 7.32 (br s, 1H),7.6 (m, 2H), 7.8 (dt, 1H), 8.5 (dd, 1H), 8.65 (dd)

Found: C, 53.6; H, 5.9; N, 9.6%

C₁₉ H₂₅ N₃ O₂ S₃ requires: C, 53.9; H, 5.95; N, 9.9%];

vii)(±)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt 101°-102° C.;

[N.M.R. (CDCl₃): 1.3-1.6 (m, 7H), 1.8-1.9(m, 1H), 2.1-2.15 (m, 1H),2.5-2.6 (m, 1H), 2.8-2.9 (m, 2H), 3.05(m, 1H), 3.1(d, 3H), 5.9(br t,1H), 7.3 (q, 1H), 7.45 (q, 1H), 7.5 (br s, 1H), 7.8 (dt, 1H), 8.15 (dt,1H), 8.4 (dd, 1H), 8.6(d, 1H), 8.8(dd, 1H), 9.0 (d, 1H)

Found C, 55.9; H, 6.3; N, 13.1%

C₂₀ H₂₆ N₄ O₂ S₂.1/2H₂ O requires: C, 56.1; H, 6.36; N, 13.1%];

viii)(±)-trans-2-(3,4-difluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt. 90°-91° C.;

[N.M.R.(CDCl₃): 1.2-1.6 (m, 6H), 1.6-2.0(m, 3H), 2.0-2.2(m, 1H), 2.4-2.6(m, 1H), 2.7-3.1 (m, 2H), 3.1 (d, 3H), 5.5 (t, 1H), 7.2-7.4 (m, 2H),7.6-7.8 (m, 2H), 8.45 (dd, 1H), 8.6(d, 1H)

Found: C, 55.6; H, 5.6; N, 9.0; S, 14.5%

C₂₁ H₂₅ F₂ N₃ O₂ S₂ requires: C, 55.6; N, 5.6; N, 9.3; S, 14.1%]; and

ix)(±)-trans-2-(5-dimethylamino-1-naphthalenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.pt 125°-126° C.

[N.M.R. (CDCl₃): 1.0-1.4 (m, 6H), 1.4-1.6 (m, 2H), 1.9-2.1 (m, 1H),2.3-2.5 (m, 1H), 2.6-2.8 (m, 2H), 2.85 (s, 6H), 2.9 (m, 1H), 3.1 (d,1H), 5.2 (br t, 1H), 7.1-7.3 (m, 4H), 7.4-7.7 (m, 3H), 8.2-8.4 (dd, 2H),8.4-8.5 (m, 2H)

Found: C, 60.3; H, 6.7; N, 9.8%

C₂₇ H₃₄ N₄ O₂ S₂ requires: C, 63.5; H, 6.7; N, 11.0%].

EXAMPLE 4

Compound 1T

To a solution of(±)-trans-2-aminoethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide(1 g, 3.6 mmol) in toluene (20 ml) and 1,2-dichlorobenzene (5 ml) wasadded 90% diglycollic anhydride (928 mg, 7.2 mmol) and the solutionheated at reflux for 3 hr. After this time the mixture was cooled andthe liquors decanted from the black tar and concentrated in vacuo togive a pale yellow oil. The oil was subjected to flash chromatographyover silica gel using methanol/ethyl acetate (5:95) as eluent to give(±)-trans-2-(3,5-dioxomorpholino)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (290 mg), as a cream solid, m.pt 181°-183° C.

[N.M.R. (CDCl₃):1.4-1.6 (m, 8H), 2.0-2.2 (m, 2H), 2.6-2.7 (m, 1H),3.1(d, 3H),3.7 (m, 1H), 3.8 (m, 1H), 4.35 (s, 4H), 7.3 (br s, 1H), 7.4(q, 1H), 7.95 (d, 1H), 8.55 (dd, 1H), 8.6 (d, 1H)

Found: C, 60.2; H, 6.6; N, 11.1; S, 7.3%

C₁₉ H₂₅ N₃ O₃ S requires: C, 60.8; H, 6.7; N, 11.2; S, 8.5%].

EXAMPLE 5

Compounds 2A to 2M

By carrying out processes similar to those described herein, moreespecially in the Examples and Reference Examples, there were preparedthe following compounds:

(±)trans-2-(propylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 81°-83° C., in the form of a foam;

(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 104°-106° C.;

(±)-trans-2-(butylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 82°-84° C., in the form of a foam;

(±)-trans-2-(fluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 105°-112° C., in the form of a foam;

(±)-trans-2-(3-cyanobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 85°-90° C., in the form of a foam;

(±)-trans-2-(3-benzenesulphonyl)aminomethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 79°-80° C., in the form of a foam;

(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 64°-65° C., in the form of a foam;

(±)-trans-2-(4-fluorobenzenesulphonyl)aminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 81°-83° C., in the form of a foam;

(±)-trans-2-(3-pyridinesulphonylaminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 58°-60° C., in the form of a foam;

(-)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 98°-99° C., [α]^(D) =-26°;

(-)-trans-2-(4-fluorobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 64°-65° C. in the form of a foam, [α]^(D) =-20.6°;

(-)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide, m.p. 90°-91° C., in the form of a foam; and

(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(4-pyridyl)cyclohexanecarbothioamide as a white solid, m.p. 146°-147° C.

REFERENCE EXAMPLE 1

To a solution of(±)-trans-2-aminoethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide(500 mg, 1.8 mmol) in ethanol (10 ml) was added, with stirring,dithiomethyl benzenesulphonyliminocarbonate (470 mg, 1.8 mmol) and themixture heated at reflux for 8 hr, cooled and concentrated in vacuo togive a brown oil. The oil was purified by flash chromatography oversilica gel using ethyl acetate/methanol (95:5) as eluent to give a paleyellow oil which was triturated with ether to give(±)-trans-2-(2-(N-benzenesulphonyl-S-methylisothioureido)ethyl)-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (280 mg), as a white solid

[N.M.R.(CDCl₃): 1.0-1.8 (m, 8H), 2.0-2.2 (m, 2H), (s, 3H), 2.6 (m, 1H),3.1(d, 3H), 3.2-3.3 (m, 2H), 7.2 (m, 2H), 7.4-7.5 (m, 3H), 7.8-8.0 (dd,2H), 8.5 (d, 1H), 8.6(d, 1H), 8.1 (br s, 1H)

Found: C, 55.9; H, 6.2; N, 11.2; S, 18.5%

C₂₃ H₃₀ N₄ O₂ S₃ requires: C, 56.3; H, 6.2; N, 11.4; S, 19.6%].

REFERENCE EXAMPLE 2

To a solution of(±)-trans-2-aminoethyl-N-methyl-1-(3-pyridyl)cyclohexane carbothioamide(500 mg, 1.8 mmol) in ethanol (10 ml) was added, with stirring,dithiomethyl methanesulphonyliminocarbonate (360 mg, 1.8 mmol) and themixture heated at reflux for 8 hr, cooled and concentrated in vacuo toan oil. The oil was purified by flash chromatography over silica gelusing ethyl acetate/methanol (95:5) as eluent to give(±)-trans-2-(2-N-methanesulphonyl-S-methylisothioureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide (220 mg), as a white solid, m. pt 74°-75° C.

[N.M.R.(CDCl₃): 1.3-1.8 (m, 7H), 2.0-2.2 (m, 2H), 2.4 (s, 3H), 2.6(m,1H), 3.0 (s, 3H), 3.05(m, 1H), 3.15 (d, 3H), 3.25 (m, 2H), 7.3 (q, 1H),7.4 (br s, 1H), 7.8 (br s, 1H), 7.9 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H)

Found: C, 49.9; H, 6.5; N, 12.6; S, 20.7%

C₁₈ H₂₈ N₄ O₂ S₃ requires: C, 50.4; H, 6.6; N, 13.11; S, 22.4%].

REFERENCE EXAMPLE 3

A solution of (±)-trans-2-cyanomethyl-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide (3 g, 10.8 mmol) in dry tetrahydrofuran (30 ml) was addeddropwise at room temperature under argon to a stirred suspension oflithium aluminium hydride (1.25 g, 33 mmol) in dry tetrahydrofuran (75ml). After the addition, the mixture was stirred at reflux for 1 hr,cooled and treated with Rochelle salt solution (20 ml) and ethyl acetate(50 ml). The layers were separated and the aqueous was extracted withethyl acetate (30 ml). The combined extracts were washed with water,dried (MgSO₄) and concentrated in vacuo to give a yellow oil which wastriturated with ether to give(±)-trans-2-(2-aminoethyl)-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide (2 g) as a yellow solid;

[N.M.R. (CDCl₃): 1.0-1.1 (m, 1H), 1.4-1.8 (m, 4H), 2.0 (m, 1H), 2.1 (m,1H), 2.5 (m, 2H), 2.7 (m, 4H), 3.1 (d, 3H), 3.15-3.3 (m, 2H), 7.25 (q,1H), 7.9 (dt, 1H), 8.4 (dd, 1H), 8.7 (d, 1H)].

REFERENCE EXAMPLE 4

A suspension of lithium aluminium hydride (135 mg, 3.54 mmol) at roomtemperature in dry tetrahydrofuran (20 ml) was treated dropwise with adry tetrahydrofuran solution (10 ml) of2-cyanomethylene-N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamide (960mg, 3.54 mmol). The mixture was stirred at room temperature for 10 mins.Water (5 ml) was added dropwise followed by ethyl acetate (50 ml). Themixture was washed with an aqueous solution of Rochelle salt (50 ml) andthe separated organic extract dried over magnesium sulphate.Concentration in vacuo yielded a yellow gum which was purified by flashchromatography over silica gel, eluting with ethyl acetate to yield apale yellow gum (610 mg, 2.23 mmol). Trituration with ether/hexaneyielded (±)-trans-2-cyanomethyl-N-methyl-1-(pyrid-3-yl)cyclohexanecarbothioamide (610 mg, 2.23 mmol), as a white solid, m.p. 177°-178° C.;

[N.M.R. (CDCl₃): 1.38-2.6 (c, 10H), 3.08-3.14 (d, 3H), 3.64-3.80 (m,1H), 7.28-7.36 (m, 1H), 7.48-7.68 (br s, 1H), 7.72-8.00 (m, 1H),8.52-8.60 (m, 1H)

Found: C, 65.5; H, 6.9; N, 15.1%

Calculated for C₁₅ H₁₉ N₃ S: C, 65.9; H, 7.0; N, 15.4%

m/z=274].

REFERENCE EXAMPLE 5

A solution of diethyl cyanomethylphosphonate (215 mg, 1.2 mmol) at roomtemperature in dry tetrahydrofuran (20 ml) was treated with a 60% oildispersion of sodium hydride (40 mg, 1 mmol). After 15 mins at roomtemperature (±)-N-methyl-2-oxo-1-(pyrid-3-yl)cyclohexane carbothioamide(245 mg, 1 mmol) was added and the resulting solution stirred for 3hours at room temperature. Ethyl acetate (50 ml) and then water (50 ml)were added to the reaction mixture. The layers were separated and theorganics washed with water (50 ml). The organic extract was dried overmagnesium sulphate and concentrated in vacuo to give a crude gum.Purification by flash chromatography, eluting with a 1:1 (v/v) mixtureof ethyl acetate/hexane gave(±)-2-cyanomethylene-N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamideas a colourless gum (190 mg, 0.7 mmol). Trituration with ether yielded awhite solid (190 mg, 0.7 mmol), m.p. 182°183° C.;

[N.M.R. (CDCl₃): 1.47-1.78 (c, 2H), 1.78-2.00 (c, 2H), 2.20-2.38 (m,1H), 2.46-2.64 (m, 1H), 2.82-2.96 (m, 1H), 3.06-3.24 (m, 1H), 3.22-3.26(d, 3H), 3.94 (s, 1H), 7.26-7.36 (m, 1H), 7.48-7.64 (m, 2H), 8.48-8.52(m, 1H), 8.52-8.58 (m, 1H)

Found: C, 66.6; H, 6.3; N, 15.7%

C₁₅ H₁₇ N₃ S: C, 66.4; H, 6.3; N, 15.5%

m/z=271].

REFERENCE EXAMPLE 6

A vigorously stirred solution of (±)-2-(pyrid-3-yl)cyclohexanone (5.5 g,30 mmol) in anhydrous tetrahydrofuran (50 ml) under argon at -15° C. wastreated with potassium t-butoxide (3.36 g, 30 mmol).

After 60 minutes at 0° C., a solution of methyl isothiocyanate (2.4 g,33 mmol) in anhydrous tetrahydrofuran (10 ml) was added during 5minutes. After 2.5 hours at 0° C. the solution was warmed to 20° C. andthen poured into a saturated aqueous brine solution (250 ml). Themixture was extracted with ethyl acetate (50 ml) and then withchloroform (3×50 ml). The combined organic extracts were dried oversodium sulphate and the concentrated in vacuo (30° C.; 14 mmHg).

The crude product was recrystallised from methanol to give(±)-N-methyl-2-oxo-1-(pyrid-3-yl)cyclohexane carbothioamide (4.8 g, 19mmol), m.p. 188°-190° C.;

[N.M.R. (CDCl₃): 1.62-2.06 (m, 4H), 2.42-2.60 (m, 2H), 2.60-2.82 (m,1H), 2.84-3.06 (m, 1H), 3.16-3.2 (d, 3H), 7.24-7.34 (ddd, 1H), 7.6-7.68(ddd, 1H), 8.43-8.47 (d, 1H), 8.48-854 (dd, 1H), 8.9-9.2 (br s, 1H)

Found: C, 62.9; H, 6.6; N, 11.3; S, 13.1%

Calculated for C₁₃ H₁₆ N₂ OS: C, 62.9; H, 6.5; N, 11.3; S, 12.9%].

REFERENCE EXAMPLE 7

A solution of (±)-trans-1-[(pyrid-3-yl)bromomethyl]cyclopentanol (10.24g, 40 mmol) in anhydrous tetrahydrofuran (500 ml) at 0° C. was treated,dropwise during 30 minutes, with a solution of silver perchlorate (9.9g, 48 mmol) in anhydrous tetrahydrofuran (50 ml). After 60 minutes at 0°C. the mixture was poured into a mixture of saturated aqueous brinesolution (500 ml) and 10% v/v aqueous sodium bicarbonate solution (500ml). The resulting mixture was filtered and then extracted with ethylacetate (2×500 ml). The combined organic extracts were washed with brineand then dried over sodium sulphate. Concentration in vacuo (30° C.; 14mmHg) afforded a crude oil which was recrystallised from cyclohexane(120 ml) to give (±)-2-(pyrid-3-yl)-cyclohexane (6.7 g, 38 mmol), m.p.78°-80° C.

[N.M.R. (CDCl₃): 1.72-2.12 (m, 4H), 2.12-2.40 (m, 2H), 2.40-2.64 (m,2H), 3.56-3.72 (dd, 1H), 7.22-7.32 (m, 1H), 7.44-7.54 (ddd, 1H),8.34-8.42 (dd, 1H), 8.46-8.54 (dd, 1H)].

REFERENCE EXAMPLE 8

A solution of 3-cyclopentylidenemethylpyridine (62.2 g, 0.39 mol) inacetone (600 ml) and water (100 ml) was treated with a solution ofconcentrated sulphuric acid (18.9 g, 0.19 mmol) in water (100 ml) at 5°C. The ice-cold solution was treated with1,3-dibromo-5,5-dimethylhydantoin (55 g, 0.19 mol) during 20 minutes.After 3.5 hours at 0° C. the mixture was treated with sodium bicarbonate(33.6 g, 0.4 mol) followed by water (2 l) and then extracted with ethylacetate (2×500 ml). The organic phase was removed and washed with 10%w/v aqueous sodium bicarbonate solution (500 ml) followed by water (200ml) and brine (200 ml). The crude extract was dried over sodium sulphateand then filtered through a column of flash silica gel (10 cm×2.4 cmdiameter). After concentration in vacuo (20° C.; 14 mmHg) the dark oilcrystallised on standing to give(±)-trans-1-[(pyrid-3-yl)bromomethyl]cyclopentanol (56 g, 0.22 mol) m.p.92°-94° C.

[N.M.R. (CDCl₃) 1.36-2.06 (c, 8H), 2.32-2.46(br s, 1H), 5.02 (s, 1H),7.24-7.34 (ddd, 1H), 8.0-8.1 (ddd, 1H), 8.52-8.56 (dd, 1H), 8.62-8.66(d, 1H)

Found: C, 51.9; H, 5.6; Br, 30.6; N, 5.5%

Calculated for C₁₁ H₁₄ BrNO: C, 51.6; H, 5.5; Br, 31.2; N, 5.5%].

REFERENCE EXAMPLE 9

A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55mol) in anhydrous tetrahydrofuran (1000 ml) at 2° C. was treated withvigorous stirring under an atmosphere of argon, with potassiumt-butoxide (61.7 g, 0.55 mol). The dark red mixture was stirred at 5° C.for 80 minutes and then treated with pyridine-3-carbaldehyde (58.9 g,0.55 mol) during a period of 20 minutes. The reaction mixture wasstirred at 0° C. for 2 hours and then at 20° C. for 18 hours. Thetetrahydrofuran was removed in vacuo (30° C.; 14 mmHg) and the residueextracted with pentane (2×500 ml). After treatment with decolourisingcharcoal (5 g), the mixture was filtered through a plug of flash silicagel (Merck 70-230 mesh; 13 cm×2 cm diameter). The filtrate wasconcentrated in vacuo (30° C., 14 mmHg; then 20° C., 0.01 mmHg) toafford 3-cyclopentylidenemethylpyridine (54 g, 0.34 mol) as an orangeoil which was used without further purification;

[N.M.R. (CDCl₃): 1.6-1.95 (m, 4H), 2.4-2.65 (m, 4H), 6.26-6.34 (m, 1H),7.16-7.25 (ddd, 1H), 7.56-7.65 (ddd, 1H), 8.52-8.52 (d, 1H)].

REFERENCE EXAMPLE 10

A 4:1 mixture of (±)-cis/trans-2-methoxy-1-(pyrid-3-yl)cyclohexanol (2g, 10 mmol), toluene and phosphorus pentoxide (3.4 g, 24 mmol) washeated at reflux for 5 hours. The mixture was then filtered and theprecipitate partitioned between 2M sodium hydroxide solution (80 ml) anddiethyl ether (25 ml). The aqueous layer was extracted with ether (3×25ml) and the combined organic extracts were dried over sodium sulphate.Concentration in vacuo afforded a crude oil which was purified by flashchromatography to give 2-(pyrid-3-yl)cyclohexanone (0.7 g, 4 mmol).

REFERENCE EXAMPLE 11

To a solution of 2.5M n-butyllithium in hexane (13.2 ml, 33 mmol) at-78° C. was added diethyl ether (15 ml) followed by a solution of3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10minutes. After 1 hour at -78° C. a solution of(±)-2-methoxycyclohexanone (3.84 g, 30 mmol) in ether (20 ml) was addeddropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at0° C. the reaction mixture was warmed to 20° C. and then poured onto ice(150 g). The mixture was extracted with ether (2×50 ml) and then thecombined organic extracts were extracted with 1N hydrochloric acid (50ml). This aqueous extract was washed with ether (20 ml) and then treatedwith 2M sodium hydroxide solution (25 ml) and extracted with ether(3×100 ml). The organic extracts were combined, washed with brine thendried over anhydrous sodium sulphate. Concentration in vacuo afforded(±)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1mixture of cis and trans isomers;

[N.M.R. (CDCl₃): 1.2-2.14 (c), 2.24-2.44 (m), 2.90-3.28 (c), 3.48-3.60(m), 7.18-7.30 (m), 7.78-7.96 (m), 8.40-8.48 (m), 8.62-8.72 (m),8.78-8.82 (m)].

The present invention includes within its scope pharmaceuticalcompositions which comprise a compound of general formula (I) or apharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable carrier or coating. In clinical practice thecompounds of the present invention may be administered rectally, but arepreferably administered parenterally, by inhalation if appropriate, or,more preferably, orally.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, one or more ofthe active compounds is, or are, admixed with at least one inert diluentsuch as starch, sucrose or lactose.

The compositions may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g. lubricating agents, such asmagnesium stearate.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, inert diluents commonly used in the art such aswater and liquid paraffin. Besides inert diluents such compositions maycomprise adjuvants, such as wetting, and suspending agents, andsweetening, flavouring, perfuming and preserving agents. Thecompositions according to the invention for oral administration alsoinclude capsules of absorbable material such as gelatin, containing oneor more of the active substances with or without the addition ofdiluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive and injectable organic esters such as ethyl oleate. Thecompositions may also contain adjuvants such as stabilising, preserving,wetting, emulisfying and dispersing agents. They may be sterilised by,for example, filtration through a bacteria-retaining filter, byincorporation in the compositions of sterilising agents, by irradiationor by heating. They may also be manufactured in the form of sterilesolid compositions, which can be dissolved in sterile water or someother sterile injectable medium immediately before use.

Compositions for inhalation may be sterile aqueous solutions which arethen nebulised or dry powders formulated in accordance with knownmethods.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing one or moreof the compounds of formula (I) or a pharmaceutically acceptable saltthereof.

The percentage of active ingredient in the composition of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration, the duration ofthe treatment, and the condition of the patient. In the adult, the dosesare generally from about 0.001 to about 50, preferably from about 0.01to about 5, mg/kg body weight per day by oral administration. Byinhalation, either as a nebulised solution or as a formulated drypowder, the preferred daily dosage is from about 0.001 to about 5,preferably from about 0.01 to about 0.5, mg/kg body weight.

The following Example illustrates pharmaceutical compositions accordingto the present invention.

COMPOSITION EXAMPLE

No. 2 size gelatin capsules each containing:

    ______________________________________                                        (±)-trans-2-benzenesulphonylaminoethyl-N-methyl-                                                      20 mg                                              1-(3-pyridyl)cyclohexane carbothioamide                                       lactose                    100 mg                                             starch                     60 mg                                              dextrin                    40 mg                                              magnesium stearate          1 mg                                              ______________________________________                                    

were prepared in accordance with the usual procedure.

We claim:
 1. A thioformamide compound of formula (I): ##STR3## in whichR represents an alkyl group; A is (1) a phenyl group, which isunsubstituted or substituted by one or more substituents selected from ahalogen atom and a cyano, nitro, trifluoromethyl, carbamoyl, carboxyl,alkoxycarbonyl and alkylsulphonyl group, or (2) a heterocyclyl groupselected from pyrid-3-yl, pyrid-4-yl, indol-3-yl and thiazol-5-yl, whichis unsubstituted or substituted by an alkyl or alkoxy group or a halogenatom;Y represents an ethylene or methylene group or a direct bond; andeither: (1) R¹ represents hydrogen and R² represents:i) a group offormula --CXNHR³, wherein R³ is an alkyl group and X is a group offormula ═NSO₂ R⁴, wherein R⁴ is an alkyl or phenyl group; or ii) a groupof formula --SO₂ R⁵, wherein R⁵ is:(a) a naphthyl or phenyl groupoptionally substituted by one or more halogen atoms, hydroxy, alkoxy,C₃₋₆ cycloalkoxy, alkyl, C₂₋₄ alkenyl, cyano, nitro, trifluoromethyl,carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino,alkoxycarbonylamino, alkanoylamino, dialkanoylamino, benzoylamino,carbamoyl, N-(optionally hydroxyalkyl)carbamoyl or N,N-di(optionallyhydroxyalkyl)carbamoyl groups, or amino or carbamoyl groupsN,N-disubstituted by a C₃₋₆ alkylene chain, one or more of whosemethylene groups may have been replaced by an oxygen or sulphur atom oran imino or alkylimino group; (b) a pyridyl or thienyl group; or (c) analkyl group optionally substituted by one or more halogen atoms, phenyl,naphthyl, pyridyl, hydroxy, alkoxy, C₃₋₆ cycloalkoxy, alkyl, C₂₋₄alkenyl, cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl, amino,alkylamino, dialkylamino, alkoxycarbonylamino, alkanoylamino,dialkanoylamino, benzoylamino, carbamoyl, N-(optionallyhydroxyalkyl)carbamoyl or N,N-di(optionally hydroxyalkyl)carbamoylgroups, or amino or carbamoyl groups N,N-disubstituted by a C₃₋₆alkylene chain, one or more of whose methylene groups may have beenreplaced by an oxygen or sulphur atom or an imino or alkylimino group;or (2) R¹ and R² both independently represent a group of formula --SO₂R⁵, as defined above;wherein all the alkyl groups or moieties arestraight-chain or branched and contain 1 to 6 carbon atoms and providedthat at least one of A or R⁵ is pyridyl; or a salt thereof.
 2. Acompound according to claim 1 in which:i) R represents a methyl or ethylgroup; ii) A represents a pyrid-3-yl or pyrid-4-yl group; iii) Yrepresents a methylene group; iv) R¹ represents a hydrogen atom; v) R³represents a methyl group; vi) R⁴ represents a methyl or phenyl group;and vii) R⁵ represents:a) a phenyl or naphthyl group optionallysubstituted by one or more halogen atoms or nitro, cyano, alkoxy ordialkylamino groups; b) a pyrid-3-yl or thien-2-yl group; or c) an alkylgroup of up to 4 carbon atoms.
 3. A compound according to claim in whichR⁵ represents:a) a phenyl or 1-naphthyl group optionally substituted byone or more fluorine or chlorine atoms or nitro, cyano, methoxy ordimethylamino groups; b) a pyrid-3-yl or thien-2-yl group; or c) amethyl group.
 4. A compound according to claim 1 which is selected fromthe group consistingof:(±)-trans-2-(N-methyl-N'-benzenesulphonylimino-ureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(N-methyl-N'-methanesulphonylimino-ureido)ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-benzenesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-methanesulphonylaminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-fluorobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-nitrobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-chlorobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-methoxylbenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(2-thiophenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(3,4-difluorobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(5-dimethylamino-1-naphthalene-sulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)-cyclohexanecarbothioamide,(±)-trans-2-(propylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(butylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(2-fluorobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(3-cyanobenzenesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(benzenesulphonyl)aminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-fluorobenzenesulphonyl)amino-ethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(3-pyridinesulphonylaminoethyl-N-ethyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(3-pyridinesulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(4-fluorobenzenesulphonyl)amino-ethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(3-pyridyl)cyclohexanecarbothioamide,(±)-trans-2-(isopropylsulphonyl)aminoethyl-N-methyl-1-(4-pyridyl)cyclohexanecarbothioamide, and pharmaceutically acceptable salts thereof.
 5. Apharmaceutical composition comprising a compound of claim 1 inassociation with a pharmaceutically acceptable carrier or diluent.
 6. Amethod for the treatment of a disorder associated with vascular,respiratory, gastrointestinal tract, urinary bladder or uterus smoothmuscle contraction in a patient which method comprises administering tothe patient an amount effective to combat said disorder of a compound asclaimed in claim 1.